The halogenation of organic compounds at a specific site or position (regiospecific halogenation) is a very difficult task. In general, hydrocarbon compounds tend to undergo halogenation to some degree at virtually every available carbon-hydrogen linkage. The random nature of this substitution generally leads to an undesirable mixture of isomers and homologs. Further, when additional reactants are employed to make the reaction more selective or specific, additional competing reactions are also likely to be encountered; when more reactants are employed there is a greater likelihood of side or competing reaction simply because there are more components in the system.
The present invention makes use of the discovery that the most efficient way to prepare alpha-substituted acyl compounds, particularly alpha-chloro acyl chlorides and acyl esters, is to begin with the corresponding carboxylic acid chloride.
The Hell-Volhard-Zelinksy (HVZ) alpha-bromination of carboxylic acids was discovered a century ago. This was based upon the observation that in the presence of a small amount of phosphorus, aliphatic carboxylic acids react smoothly with bromine to yield a compound in which the alpha-hydrogen has been replaced by a bromine substituent. Only recently has work related to regiospecific halogenation of acyl compounds focused upon the alpha-substitution of halogens other than bromine, and in particular to extending the HVZ reaction to alpha-chloro substitution. It was then quickly appreciated that the propensity of chlorine to undergo competing free radical reactions under HVZ conditions required the development of specialized procedure that would favor the ionic alpha-substitution process. See Little, Saxton, et al., Journal of the American Chemical Society 91 7098 (1969); U.S. Pat. No. 3,584,036 to Saxton, et. al., both of which relate to the solution of this problem.
Ogata, et. al., have developed a procedure which employs the addition of gaseous chlorine to a neat aliphatic acid at 140.degree. C. in the presence of a strong acid catalyst and oxygen. Ogata suggests that the preferred catalyst is chlorosulfonic acid (10 mol % of the carboxylic acid) in combination with the oxygen gas. See Ogata, et al., J. Org. Chem., 40 2960 (1975); Ogata, et al., Tetrahedron 26 5929 (1970); Ogata, et al., Nippon Kagaku Kaishi 1517 (1975) [Chem. Abstr. 83 178239 (1975)]; Ogata, et al., Japanese Patent 75-135024; Ogata, et al., Japanese Patent 74-24913. The method works particularly well for short chain (C.sub.2 -C.sub.6) carboxylic acids. However, for chain lengths greater than C.sub.6, the reaction is adequate, but sub-optimal. There is no suggestion here of halogenating acyl halide starting materials.
Crawford, U.S. Pat. No. 4,148,811, issued Apr. 10, 1979; U.S. Pat. No. 4,368,140, issued Jan. 11, 1983; J. Org. Chem. 48 1364 (1983); describes the regiospecific halogenation of long chain, as well as short chain, carboxylic acids, carboxylic acid halides, and acid anhydrides, employing a modification of Ogata's reaction. The major change is the use of a free radical inhibitor, such as 7,7,8,8-tetracyanoquinodimethane (TCNQ), in place of the oxygen gas. This change (TCNQ at 0.5 mol% in place of the oxygen) resulted in an improved reaction that was unaffected by chain length. (As stated above the use of oxygen and chloranil as taught by Ogata does not perform well on chain length greater than about C.sub.6.) While Crawford states that this system can be used with the carboxylic acid, acid halide and acid anhydride, he states that temperatures above 130.degree. C. must be employed if elemental chlorine is used as the halogen source. He also describes the many quinone or "quinone-like" structures which can be used as free radical inhibitors.
U.S. Pat. No. 3,880,923, Scheider, et al., issued Apr. 29, 1975, describes an improved process for the production of alpha-chloro-carboxylic acid chlorides by reacting a carboxylic acid chloride with chlorine at an elevated temperature in the presence of sulfuric acid.
U.S. Pat. No. 4,169,847, Degischer, issued Oct. 2, 1979, describes an improved process for the production of alpha-chloro-alkanoyl chlorides by reacting alkanoyl chlorides with chlorine at an elevated temperature in the presence of chlorosulphonic acid as a catalyst.
U.S. Pat. No. 3,152,055, Katzschmann, issued Oct. 6, 1964, describes production of aromatic chlorocarboxylic acid chlorides by using an ester as a starting material.
The methods of the present invention are simpler and more efficient, and possesses the following advantages versus those described in the art-disclosed processes: The reaction takes place under less rigorous conditions particularly when using elemental chlorine, goes more quickly, yields less alpha,alpha-dichloro material (and other products of competing reactions), and works efficiently regardless of the chain length of the starting material.
In particular, the present invention provides a marked improvement over the processes disclosed in U.S. Pat. Nos. 3,584,036; 4,148,811; and 4,368,140; discussed above.
With respect to the processes described by Crawford, the present method allows the use of elemental chlorine at temperatures significantly below 130.degree. C. This is accomplished by employing the carboxylic acid halide, particularly the carboxylic acid chloride, as the starting material. Certain of the present methods allow excellent results to be obtained by employing commercial antioxidants in place of the more expensive free radical inhibitors of Crawford if the carboxylic acid chloride is used as a starting material; elemental chlorine and lower temperatures may also be employed.
With respect to the processes described by Ogata, the present method is made more efficient by beginning with the carboxylic acid halide, particularly the carboxylic acid chloride. This means that significantly less rigorous conditions may be employed. For example, if chloranil is employed as a free radical inhibitor in a process which begins with the free acid, and in a process which begin with the acid chloride, a higher yield can be obtained with a lower reaction temperature by employing the acid chloride (i.e., by following the teachings of the present invention).
The same is true if air or elemental oxygen are employed. If the acid chloride is used as the starting material and air or elemental oxygen are employed alone (without the free radical inhibitors employed by Ogata and Crawford, chloranil or TCNQ), the methods above can be run with equivalent results.